Abstract Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic-based heart disease leading to sudden cardiac death in young people. ARVC is termed a ?disease of the desmosome? as 40% of ARVC harbor mutations and/or loss of desmosomal components. However, the mechanisms that control desmosomal protein levels and function in health and disease are undefined. We identified CSN6, which is subunit 6 of the COP9 signalosome family, in a yeast-two-hybrid screen as a novel desmosomal (desmoplakin, DSP) interacting protein in the adult human heart. Traditional functions of the CSN complex are to ?turn off? ubiquitination mediated protein degradation via de-neddylation; however, the role for CSN6 in the heart is undefined. We believe that CSN6 uniquely protects the cardiac desmosome from degradation and its loss accelerates desmosome destruction as (i) CSN6 co-localizes to desmosomal junctions, (ii) CSN6 co- immunoprecipitates with desmosomal proteins and (iii) hearts from novel cardiac-specific CSN6 knockout (CSN6-cKO) mice display selective loss of desmosomal protein levels (and its primary target, connexin43). CSN6 loss is a trigger for ARVC as CSN6-cKO mice exhibit sudden death and cardiac disease features associated with a biventricular form of ARVC, similar to our classic biventricular (DSP-cKO) model of ARVC. CSN6 and DSP-cKO hearts both selectively display underlying hyper-accumulation of protein degradation machinery at the cell junction, specifically linking CSN6 pathways to the desmosome. CSN6 pathways are relevant to human ARVC as (i) CSN6 levels are down-regulated in ARVC hiPSC-derived cardiac cells that exhibit striking desmosomal defects and arrhythmogenic behavior and (ii) CSN6 localization is lost from cell junctions in a cardiac biopsy from an ARVC patient harboring desmosomal (DSP (R315C) and plakophilin-2 (PKP2 IVS10-1 G>C) mutations. Yeast and in silico modeling assays reveal that this DSP R315C mutation is sufficient to abrogate DSP binding to CSN6. However, CSN6 also associates with PKP2, suggesting that the PKP2 mutation may also play a role in these mechanisms (two-hit hypothesis). In terms of the CSN6- desmosomal complex, our data suggests that other CSNs may compartmentalize (?subcomplex?) with CSN6 at the desmosome and their localization may be dependent on CSN6. We hypothesize that CSN6 targets an enzymatically active CSN subcomplex to the cardiac desmosome to protect desmosomes from degradation via neddylation, and dysregulation of this mechanism triggers ARVC. We aim to: (i) define the CSN6 subcomplex members, which protect the desmosome from degradation in cardiomyocytes, (ii) determine the effects of inhibiting the underlying hyper-accumulated protein degradation in cardiac-specific CSN6 and DSP knockout mice and (iii) understand the role of the desmosome-CSN6 interaction by characterizing two novel knockin mouse models that harbor human ARVC-associated desmosomal mutations that interrupt binding to CSN6.